New therapeutics that target gene expression such as nucleic acid (NA) based constructs show great promise for treating complex diseases more effectively. However a major roadblock to the implementation of these compounds for clinical use is their efficient delivery into tissues and cells which is impeded due to their highly charged nature and inability to pass across the plasma membrane. Here we propose to formulate and test a novel delivery system based on chemically modified gold nanoparticles (GNPs) for delivery of an NA-based compound (signal transducer and activator of transcription 3 decoy oligonucleotide (STAT3d)) that has shown effectiveness in the treatment of head and neck squamous cell carcinoma (HNSCC). The novel carrier system is expected to overcome multiple limitations currently faced by this type of technology in that it (1) allows the therapeutic NA to e administered systemically after IV injection, (2) allows the NA to preferentially target cancer cells, (3) allows the NA to permeate the cell membrane, (4) allows the molecule to be tracked via fluorescence imaging, and (5) allows for the additive benefit of radiation sensitization to be conferred after uptake of the GNP-based delivery system in tumor cells. Development of the novel NA-based therapeutic (NA- GNP-STAT3d) will be accomplished through the following specific aims: (1) optimization and characterization of a nucleolin-targeted oligonucleotide (ODN)/gold nanoparticle (GNP) delivery system (NA-GNP-STAT3d), and (2) mapping the efficacy of the NA-GNP-STAT3d system in attenuating STAT3d-mediated gene expression in HNSCC and testing the combined effect of STAT3d and GNP-mediated radiosensitization on the viability of HNSCCs in culture.